In keeping with the objectives of the U01 RFA we propose 3 large clinical studies that are ideally suited for performance by a collaborative consortium and significantly advance our understanding of the interconnected pathologies of chronic pancreatitis (CP), pancreatic cancer (PC), and diabetes mellitus (DM). 1) Type 2 DM (T2DM) is considered purely a disorder of the endocrine pancreas. Our novel observation is that T2DM causes an exocrine pancreatopathy (EP), a new class of pancreatic affliction defined by marked, non-inflammatory pancreatic fibrosis associated with exocrine dysfunction. Diabetic EP (DEP) mimics CP and may predispose to PC. By studying autopsy and resected pancreata from diabetics and controls for both EP changes and preneoplastic lesions we expect to show that DEP and CP are distinct entities, and that DEP defines a high-risk group for PC among T2DM subjects. 2) Late-onset DM is a high-risk group for PC. The key to clinical use of this knowledge lies in distinguishing T2DM from PC-DM. In autopsy and resected pancreata we will study changes in islet morphology to establish that PC-DM is a unique form of pancreatogenic DM. We will also validate our preliminary observation that PC-DM has a blunted pancreatic polypeptide (PP) response to mixed meal compared to T2DM. In persons with T2DM and controls we will measure fasting and post-mixed meal plasma levels of insulin, c-peptide and PP to show that T2DM and pancreatogenic DM have unique hormonal signatures that distinguish T2DM from PC- DM. 3) Current diagnostic tests detect anatomic and functional changes of advanced CP. Our pilot data demonstrate that markers of inflammation in pancreatic juice (PJ) have the potential for early and accurate diagnosis of CP. Their suppression by aspirin (ASA) may indicate a role for ASA in the treatment of CP. We will measure secretin stimulated PGE2, lipase and bicarbonate levels in PJ and blood in CP, early or minimal change CP (MCCP), DEP and controls to validate the utility of PJ PGE2 for diagnosis of CP and MCCP. Furthermore, we will measure PJ PGE2 levels again after administration of ASA or placebo to participants with CP or MCCP. We expect to show that ASA decreases PJ PGE2 levels in these groups, providing rationale for clinical trials of COX-2 inhibition to prevent progression of MCCP/CP. Validation of our novel hypotheses will have significant impact on our understanding of pancreatic fibrosis, lead to clinical tests to distinguish T2DM from PC- DM, redefine our approach to early diagnosis of CP and provide insights into therapeutic approaches to slow progression of CP. Done in the U01 setting, these studies will lead to rapid acquisition and dissemination of new knowledge.